Emerging evidence suggests that an epigenefic misregulafion of the genome, including brain region-specific altered DNA promoter methylafion, is associated with the neuropathological manifestafions of alcohol abuse and dependence. DNA (cytosine) methylation generally has been regarded as a highly stable epigenefic mark ttiat ensures and maintains neuronal phenotype identity. However, the epigenfic DNA marking is highly dynamic and requires the action of a family of DNA-methyltransferases (DNMT) and an active DNAdemethylation pathway (base excision repair [BER] pathway) that includes 5methyl cytosine (5MC) hydroxylafion by a ten-eleven-translocation (TET) and deaminafion by an apolipoprotein B mRNA edifing enzyme (Apobec). Our preliminary studies in bipolar (BP) disorder and major depressed (MD) pafients who are also chronic alcoholics show decreased DNMT and a marked increase of TET-1 expression in the prefrontal cortex compared to controls. In BP and MD patients with comorbid alcoholism, there is also increased 5-hydroxyMC at GAD67 and BDNF promoters. The objective of our study is to investigate the expression and promoter binding of components of the DNAmethylafion and DNA-demethylafion network in corticolimbic structures of chronic uncomplicated alcoholics (no developmental disorders, no other psychiatric and neurological disorders) who consumed greater than 80 g of ethanol/day, obtained from the New South Wales Tissue Resource Center (see attached letter). Our working hypothesis is that DNA-methylafion/demethylafion dynamics may be involved in behavioral aspects of alcohol exposure in part through epigenetically mediated disrupfion of the balance between glutamatergic /GABAergic transmission and synapfic plasficity at corticolimbic circuit neurons. Tesfing this hypothesis in a cohort of uncomplicated chronic alcoholic subjects will reveal novel alcohol sensitive targets with obvious important therapeufic and public health implications, protein networks in human brain has obvious therapeutic and public health implications.